N-alkyl-N-phenyl-quinoline-3-carboxamides are a promising class of compounds being evaluated in clinical trials against different classes of diseases, e.g. autoimmune diseases and cancer.
N-alkyl-N-phenyl-quinoline-3-carboxamides such as paquinimod (herein below also referred to as A), laquinimod (herein below also referred to as B), and tasquinimod (herein below also referred to as C), have been prepared by a method involving distillation of the volatiles from a mixture comprising an ester, aniline and an aliphatic solvent such as n-heptane or n-octane.

This method is described in U.S. Pat. No. 6,875,869.
The prior art synthetic protocol (Org. Process. Res& Dev. 2007, 11, 674-680) for N-alkyl-N-phenyl-quinoline-3-carboxamides such as paquinimod (A), laquinimod (B), and tasquinimod (C) is exemplified with synthesis of paquinimod in Scheme 1. The route starts with an anthranilic acid 1 which is transformed into an isatoic anhydride 2. The isatoic anhydride is methylate to give 3, which is condensed with dimethylmalonate to give the corresponding methyl ester 4. The methyl ester is subsequently condensed with the appropriate aniline, to give the desired final compound.

This manufacturing method is short and avoids the use of expensive reagents. All intermediates are stable and easy to isolate in high purity by precipitation and filtration. The main impurity in the final condensation step is remaining alkyl ester. Alternative methods, such as carbodiimide mediated coupling between a carboxylic acid and aniline, or the condensation of N-alkyl-N-phenyl-malonamic acid methyl ester with an isatoic anhydride (U.S. Pat. No. 5,912,349) are either longer or yield product of lower purity.
The final condensation step is an equilibrium (Scheme 2) that favors the alkyl ester and a reaction mechanism involving a ketene intermediate 5 has been strongly indicated (J. Org. Chem. 2006, 71, 1658-1667 and J Phys. Chem. A 2008, 112, 4501-4510).

Usually formation of amides from esters and anilines requires very high reaction temperatures that also cause extensive byproduct formation. The above-mentioned reaction is enabled at moderate temperatures by the ability of 4 to unimolecularly form the ketene intermediate 5 instead of a tetrahedral intermediate. The method, which is described e.g. in U.S. Pat. No. 6,875,869, comprises charging the reactor with an appropriate ester and an aniline derivative in an aliphatic solvent such as n-heptane or n-octane. The equilibrium is driven towards the desired product by distilling off the solvent and any formed alcohol. After complete reaction the mixture is cooled and the precipitated raw product is isolated by filtration.
Unlike most other reactions where esters are transformed into thermodynamically more stable amides this particular reaction needs a very efficient removal of formed alcohol in order to give a high yield.
The method described above has been used for GMP (Good Manufacturing Practice) manufacturing of paquinimod, laquinimod and tasquinimod.